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Rapid CommunicationShort Communication

Drug Interaction Between Simvastatin and Itraconazole in Male and Female Rats

Michi Ishigami, Kiyoshi Kawabata, Wataru Takasaki, Toshihiko Ikeda, Toru Komai, Kiyomi Ito and Yuichi Sugiyama
Drug Metabolism and Disposition July 2001, 29 (7) 1068-1072;
Michi Ishigami
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Kiyoshi Kawabata
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Wataru Takasaki
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Toshihiko Ikeda
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Toru Komai
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Kiyomi Ito
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Yuichi Sugiyama
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Abstract

Taking into account the species and sex differences in drug interactions based on the inhibition of cytochrome P450 (P450)-mediated drug metabolism, we examined whether the interaction between simvastatin and itraconazole observed in humans could also occur in rats, the most commonly used animal species for pharmacokinetic studies. Itraconazole inhibited the in vitro metabolism of simvastatin in female rat liver microsomes, but not in male rat liver microsomes. Using anti-P450 antisera, the main P450 isozyme responsible for the metabolism of simvastatin was identified as CYP3A in female rats and CYP2C11 in male rats. Therefore, the sex difference in the inhibition of simvastatin metabolism by itraconazole seems to be caused by a difference in the P450 isozymes responsible for the metabolism of simvastatin in male and female rats and the different ability of itraconazole to inhibit CYP3A and CYP2C11. In addition, the effect of itraconazole on the pharmacokinetics of simvastatin in rats was also investigated. The area under the curve value of simvastatin was increased approximately 1.6-fold by the concomitant use of itraconazole (50 mg/kg) in female rats, whereas in male rats, itraconazole had no effect. In conclusion, it was found that the results obtained in male rats did not reflect the results in humans as far as the inhibition of simvastatin metabolism by itraconazole was concerned. The P450 isozymes involved in the metabolism of drugs should be taken into consideration when rats are used as a model animal for humans in the investigation of drug interactions.

Footnotes

  • Abbreviations used are::
    HMG-CoA
    3-hydroxy-3-methylglutaryl-coenzyme A
    V0
    initial formation rate
    HPLC
    high-performance liquid chromatography
    TLC
    thin-layer chromatography
    CMC
    carboxymethylcellulose
    AUC
    area under the curve
    • Received January 2, 2001.
    • Accepted April 10, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (7)
Drug Metabolism and Disposition
Vol. 29, Issue 7
1 Jul 2001
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Rapid CommunicationShort Communication

Drug Interaction Between Simvastatin and Itraconazole in Male and Female Rats

Michi Ishigami, Kiyoshi Kawabata, Wataru Takasaki, Toshihiko Ikeda, Toru Komai, Kiyomi Ito and Yuichi Sugiyama
Drug Metabolism and Disposition July 1, 2001, 29 (7) 1068-1072;

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Rapid CommunicationShort Communication

Drug Interaction Between Simvastatin and Itraconazole in Male and Female Rats

Michi Ishigami, Kiyoshi Kawabata, Wataru Takasaki, Toshihiko Ikeda, Toru Komai, Kiyomi Ito and Yuichi Sugiyama
Drug Metabolism and Disposition July 1, 2001, 29 (7) 1068-1072;
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